Increases in [3H]Muscimol and [3H]Flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to α4 and γ2S mRNA levels respectively

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dc.contributor.authorVerdurand, Men_AU
dc.contributor.authorFillman, SGen_AU
dc.contributor.authorWeickert, CSen_AU
dc.contributor.authorZavitsanou, Ken_AU
dc.date.accessioned2020-03-24T05:53:07Zen_AU
dc.date.available2020-03-24T05:53:07Zen_AU
dc.date.issued2013-01-08en_AU
dc.description.abstractBackground GABAA receptors (GABAAR) are composed of several subunits that determine sensitivity to drugs, synaptic localisation and function. Recent studies suggest that agonists targeting selective GABAAR subunits may have therapeutic value against the cognitive impairments observed in schizophrenia. In this study, we determined whether GABAAR binding deficits exist in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia and tested if changes in GABAAR binding are related to the changes in subunit mRNAs. The GABA orthosteric and the benzodiazepine allosteric binding sites were assessed autoradiographically using [3H]Muscimol and [3H]Flumazenil, respectively, in a large cohort of individuals with schizophrenia (n = 37) and their matched controls (n = 37). We measured, using qPCR, mRNA of β (β1, β2, β3), γ (γ1, γ2, γ2S for short and γ2L for long isoform, γ3) and δ subunits and used our previous measurements of GABAAR α subunit mRNAs in order to relate mRNAs and binding through correlation and regression analysis. Results Significant increases in both [3H]Muscimol (p = 0.016) and [3H]Flumazenil (p = 0.012) binding were found in the DLPFC of schizophrenia patients. Expression levels of mRNA subunits measured did not show any significant difference in schizophrenia compared to controls. Regression analysis revealed that in schizophrenia, the [3H]Muscimol binding variance was most related to α4 mRNA levels and the [3H]Flumazenil binding variance was most related to γ2S subunit mRNA levels. [3H]Muscimol and [3H]Flumazenil binding were not affected by the lifetime anti-psychotics dose (chlorpromazine equivalent). Conclusions We report parallel increases in orthosteric and allosteric GABAAR binding sites in the DLPFC in schizophrenia that may be related to a “shift” in subunit composition towards α4 and γ2S respectively, which may compromise normal GABAergic modulation and function. Our results may have implications for the development of treatment strategies that target specific GABAAR receptor subunits. © 2013 Verdurand et al.en_AU
dc.identifier.articlenumbere52724en_AU
dc.identifier.citationVerdurand, M., Fillman, S. G., Weickert, C. S., & Zavitsanou, K. (2013). Increases in [3H] muscimol and [3H] flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to α4 and γ2S mRNA levels respectively. PLOS ONE, 8(1), e52724. doi:10.1371/journal.pone.0052724en_AU
dc.identifier.govdoc8894en_AU
dc.identifier.issn1932-6203en_AU
dc.identifier.issue1en_AU
dc.identifier.journaltitlePLOS ONEen_AU
dc.identifier.urihttps://doi.org/10.1371/journal.pone.0052724en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/9221en_AU
dc.identifier.volume8en_AU
dc.language.isoenen_AU
dc.publisherPLOS (Public Library of Science)en_AU
dc.subjectReceptorsen_AU
dc.subjectHippocampusen_AU
dc.subjectMental disordersen_AU
dc.subjectCerebral cortexen_AU
dc.subjectBrainen_AU
dc.subjectDrugsen_AU
dc.titleIncreases in [3H]Muscimol and [3H]Flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to α4 and γ2S mRNA levels respectivelyen_AU
dc.typeJournal Articleen_AU
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